tbuckley/cabot-search huggingface dataset:
Perivascular localized cells commit erythropoiesis in PDGF‐B‐expressing solid tumors
Authors: Kayoko Hosaka, Chenchen Wang, Shiyue Zhang, Xue Lv, Takahiro Seki, Yin Zhang, Xu Jing, Jieyu Wu, Qiqiao Du, Xingkang He, Yulong Fan, Xuan Li, Makoto Kondo, Masahito Yoshihara, Hong Qian, Lihong Shi, Ping Zhu, Yuanfu Xu, Yunlong Yang, Tao Cheng, Yihai Cao
Journal: Cancer Communications (2023)

Abstract Background Tumors possess incessant growth features, and expansion of their masses demands sufficient oxygen supply by red blood cells (RBCs). In adult mammals, the bone marrow (BM) is the main organ regulating hematopoiesis with dedicated manners. Other than BM, extramedullary hematopoiesis is discovered in various pathophysiological settings. However, whether tumors can contribute to hematopoiesis is completely unknown. Accumulating evidence shows that, in the tumor microenvironment (TME), perivascular localized cells retain progenitor cell properties and can differentiate into other cells. Here, we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis. Methods To test if vascular cells can differentiate into RBCs, genome‐wide expression profiling was performed using mouse‐derived pericytes. Genetic tracing of perivascular localized cells employing NG2‐CreERT2:R26R‐tdTomato mouse strain was used to validate the findings in vivo. Fluorescence‐activated cell sorting (FACS), single‐cell sequencing, and colony formation assays were applied for biological studies. The production of erythroid differentiation‐specific cytokine, erythropoietin (EPO), in TME was checked using quantitative polymerase chain reaction (qPCR), enzyme‐linked immunosorbent assay (ELISA, magnetic‐activated cell sorting and immunohistochemistry. To investigate BM function in tumor erythropoiesis, BM transplantation mouse models were employed. Results Genome‐wide expression profiling showed that in response to platelet‐derived growth factor subunit B (PDGF‐B), neural/glial antigen 2 (NG2) + perivascular localized cells exhibited hematopoietic stem and progenitor‐like features and underwent differentiation towards the erythroid lineage. PDGF‐B simultaneously targeted cancer‐associated fibroblasts to produce high levels of EPO, a crucial hormone that necessitates erythropoiesis. FACS analysis using genetic tracing of NG2 + cells in tumors defined the perivascular localized cell‐derived subpopulation of hematopoietic cells. Single‐cell sequencing and colony formation assays validated the fact that, upon PDGF‐B stimulation, NG2 + cells isolated from tumors acted as erythroblast progenitor cells, which were distinctive from the canonical BM hematopoietic stem cells. Conclusions Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell‐derived erythroid cells within TME. Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.
Imsidolimab, an anti-interleukin-36 receptor monoclonal antibody, for the treatment of generalized pustular psoriasis: results from the phase II GALLOP trial
Authors: Richard B Warren, Adam Reich, Andrzej Kaszuba, Waldemar Placek, Christopher E M Griffiths, Jihao Zhou, Bruce Randazzo, Paul Lizzul, Johann E Gudjonsson
Journal: British Journal of Dermatology (2023)

Abstract Background Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that can be severe, debilitating and life threatening. Uncontrolled activation of interleukin (IL)-36 proinflammatory activity may underlie the pathogenesis of GPP. Currently, GPP-specific treatment options are limited. Objectives To evaluate the efficacy and safety of the anti-IL-36 receptor antibody imsidolimab in patients with GPP. Methods In an open-label, single-arm, multiple-dose study, patients with GPP were treated with imsidolimab to assess clinical efficacy, tolerability and safety. Patients received an intravenous dose of imsidolimab 750 mg on day 1, followed by three subcutaneous doses of imsidolimab 100 mg administered on days 29, 57 and 85. The primary efficacy endpoint was the proportion of patients who achieved a clinical response at weeks 4 and 16 following treatment with imsidolimab, as measured by the Clinical Global Impression scale. Results Eight patients were enrolled and six completed the study. Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29 and through day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. No patient discontinued the study owing to a nonserious TEAE. Two patients experienced serious adverse events (SAEs); no deaths were reported. Conclusions Imsidolimab demonstrated a rapid and sustained resolution of symptoms and pustular eruptions in patients with GPP. It was generally well tolerated, with an acceptable safety profile, and is advancing to phase III trials. These data support the targeting of IL-36 signalling with a specific antibody – imsidolimab – as a therapeutic option for this severely debilitating condition.
Dupilumab improves patient-reported symptoms and health-related quality of life in children aged 6–11 years with severe atopic dermatitis
Authors: Carsten Flohr, Alan D Irvine, Michael J Cork, Eric L Simpson, Andreas Wollenberg, Mette Deleuran, Amy  Praestgaard, Ryan B Thomas, Ana B Rossi
Journal: British Journal of Dermatology (2023)

This was a post-hoc analysis of patient-reported outcomes from the LIBERTY AD PEDS randomized, double-blind, placebo-controlled, phase III trial of dupilumab + topical corticosteroids (TCS) in 367 children aged 6–11 years with severe atopic dermatitis (AD). At week 16, significantly more patients treated with dupilumab vs. placebo achieved a Patient-Oriented Eczema Measure (POEM) score of 0/1 (‘clear skin’/‘almost clear skin’), and significantly more reported Children’s Dermatology Life Quality Index (CDLQI) scores of 0/1 (‘no effect on life’). Significantly more patients achieved a minimal clinically important difference (≥ six-point reduction) in POEM and in CDLQI. Dupilumab (vs. placebo) + TCS resulted in clinically meaningful improvements in patients’ assessment of AD symptoms and quality of life.
Abstract A44: The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis
Authors: Peter Lyon, Praveen Singh, Byron Fang, Victoria Strippoli, Sabita Roy, Luisa Cimmino
Journal: Blood Cancer Discovery (2023)

Abstract TET2 loss-of-function mutations induce a pre-malignant state known as clonal hematopoiesis of indeterminate potential (CHIP). CHIP occurs in approximately 10% of people over 65 years of age and confers a 10-fold greater risk of developing hematological malignancy. Several environmental factors, including radiation, sleep deprivation, atherosclerosis, and diet, have been associated with the expansion of pre-malignant clones in CHIP patients. Tet2-deficiency in mice has also been shown to trigger a pro-inflammatory state with increased intestinal permeability and accelerated myeloid expansion. Gut microbes exert an influence on host disease progression through the synthesis of many compounds including short-chain fatty acids (SCFAs), which promote gut barrier integrity. Dietary levels of one-carbon metabolites and cofactors, including methionine and folate, have been found to alter gut microbial composition in disease-free adults and influence SCFA production in the gut in murine models. Given the connection between diet, SCFAs and gut permeability, we sought to determine the impact of dietary one-carbon metabolites on gut microbial composition and function in a murine model of pre-malignant hematopoiesis. We performed competitive bone marrow transplantation assays in mice fed diets with altered one-carbon metabolite supplementation, such as high and low folate or methionine. We found that differential supplementation with these one-carbon metabolites did not influence the competitiveness of Tet2-deficient hematopoietic cells, however, increased dietary methionine promoted a myeloid lineage differentiation bias and an elevation in circulating pro-inflammatory cytokines. After 8 months of dietary treatment, fecal samples were collected, and shotgun sequencing was performed to examine the role of one-carbon metabolite levels on gut microbial diversity. Alterations in dietary methionine and folate caused significant changes to gut microbial composition in Tet2-deficient mice. High folate or methionine supplementation led to a decrease in the ratio of Firmicutes to Bacteroidetes and high folate supplementation was also associated with decreased alpha diversity and a decrease in SCFA-producing bacteria in the gut. These studies highlight the potential influence of dietary one-carbon metabolites on the microbiome and inflammatory microenvironment of pre-malignant hematopoiesis. Citation Format: Peter Lyon, Praveen Singh, Byron Fang, Victoria Strippoli, Sabita Roy, Luisa Cimmino. The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A44.
Abstract A03: Mitochondrial dynamics alterations in BH3 mimetics resistance in acute myeloid leukemia
Authors: Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Evripidis Gavathiotis, Iannis Aifantis
Journal: Blood Cancer Discovery (2023)

Abstract BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL-1 are in clinical trials. Yet, resistance to single or combinatorial BH3 mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy and mitochondrial dynamics regulators sensitizes AML cells to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), which is essential in AML, while its protein levels positively correlate with drug resistance in patients with AML. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. Genetic or chemical targeting of MFN2, or global pharmacologic inhibition of autophagy, synergizes with BH3 mimetics and is a promising strategy to circumvent resistance in AML. Citation Format: Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Evripidis Gavathiotis, Iannis Aifantis. Mitochondrial dynamics alterations in BH3 mimetics resistance in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A03.
Abstract IA03: Inducing apoptosis in leukemia stem cells by targeting metabolism
Authors: Courtney Jones
Journal: Blood Cancer Discovery (2023)

Abstract Outcomes for patients with acute myeloid leukemia (AML) remain poor in part due to the inability of current therapeutic regimens to fully eradicate disease initiating leukemia stem cells (LSCs). We and others have shown that LSCs have unique and targetable metabolic vulnerabilities that can be exploited to induce apoptosis and kill this essential cell population. Interestingly the metabolic vulnerabilities that exist in LSCs appear to be highly dependent on the stage of disease pathogenesis, mutation status, and cellular state, suggesting that accounting for multiple biological factors is required when targeting metabolism in AML. Citation Format: Courtney Jones. Inducing apoptosis in leukemia stem cells by targeting metabolism [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA03.
Psychedelics as Transformative Therapeutics
Authors: Bryan L. Roth, Ryan H. Gumpper
Journal: American Journal of Psychiatry (2023)

Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of intractable neuropsychiatric conditions. However, historically most of the basic science has utilized these compounds as probes to interrogate various endogenous neurotransmitter systems-mainly the serotonin 5-HT2A receptor. With the renewed interest in utilizing these compounds as therapeutics and the explosion in clinical trials, psychedelics have been purported to treat many neuropsychiatric disorders, including depression, cluster headaches, migraines, anxiety, and obsessive-compulsive disorder. It is therefore imperative to understand the biology and pharmacology behind their therapeutic mechanisms as well as expose any potential pitfalls in their widespread use as treatments. This review covers the latest advances in understanding the biological mechanisms, the newest efforts in drug discovery, and potential pitfalls when it comes to utilizing this class of compounds as emerging therapeutics.
Extrachromosomal circular MiR-17-92 amplicon promotes HCC
Authors: Sailan Zou, Shihan Chen, Guocheng Rao, Guixiang Zhang, Meilin Ma, Boqiang Peng, Xiao Du, Wei Huang, Weiqiang Lin, Yan Tian, Xianghui Fu
Journal: Hepatology (2023)

Background and Aims: Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes and emerge as a class of crucial yet less characterized oncogenic drivers. However, the structure, composition, genome-wide frequency, and contribution of eccDNAs in HCC, one of the most fatal and prevalent cancers, remain unexplored. In this study, we provide a comprehensive characterization of eccDNAs in human HCC and demonstrate an oncogenic role of microRNA (miRNA)-17-92-containing eccDNAs in tumor progression. Approach and Results: Using the circle-sequencing method, we identify and characterize more than 230,000 eccDNAs from 4 paired samples of HCC tumor and adjacent nontumor liver tissues. EccDNAs are highly enriched in HCC tumors, preferentially originate from certain chromosomal hotspots, and are correlated with differential gene expression. Particularly, a series of eccDNAs carrying the miRNA-17-92 cluster are validated by outward PCR and Sanger sequencing. Quantitative PCR analyses reveal that miRNA-17-92-containing eccDNAs, along with the expression of their corresponding miRNAs, are elevated in HCC tumors and associated with poor outcomes and the age of HCC patients. More intriguingly, exogenous expression of artificial DNA circles harboring the miR-17-92 cluster, which is synthesized by the ligase-assisted minicircle accumulation method, can significantly accelerate HCC cell proliferation and migration. Conclusions: These findings delineate the genome-wide eccDNAs profiling of HCC and highlight the functional significance of miRNA-containing eccDNAs in tumorigenesis, providing insight into HCC pathogenesis and cancer therapy, as well as eccDNA and miRNA biology.
Pathway to global elimination of hepatitis B: HBV cure is just the first step
Authors: Jessica Howell, Chris Seaman, Jack Wallace, Yinzong Xiao, Nick Scott, Jane Davies, Teresa de Santis, Danjuma Adda, Manal El-Sayed, Jordan J. Feld, Edward Gane, Karine Lacombe, Olufunmilayo Lesi, Rosmawati Mohamed, Marcelo Silva, Thomas Tu, Peter Revill, Margaret E. Hellard
Journal: Hepatology (2023)

Hepatitis B (HBV) is a major cause of global morbidity and mortality, and the leading cause of liver cancer worldwide. Significant advances have recently been made toward the development of a finite HBV treatment that achieves permanent loss of HBsAg and HBV DNA (so-called "HBV cure"), which could provide the means to eliminate HBV as a public health threat. However, the HBV cure is just one step toward achieving WHO HBV elimination targets by 2030, and much work must be done now to prepare for the successful implementation of the HBV cure. In this review, we describe the required steps to rapidly scale-up future HBV cure equitably. We present key actions required for successful HBV cure implementation, integrated within the World Health Organization (WHO) Global Health Sector Strategy (GHSS) 2022-2030 framework. Finally, we highlight what can be done now to progress toward the 2030 HBV elimination targets using available tools to ensure that we are preparing, but not waiting, for the cure.
Probiotics to improve the gut microbiome in premature infants: are we there yet?
Authors: Emily M. Mercer, Marie-Claire Arrieta
Journal: Gut Microbes (2023)

Gut microbiome maturation in infants born prematurely is uniquely influenced by the physiological, clinical, and environmental factors surrounding preterm birth and early life, leading to altered patterns of microbial succession relative to term infants during the first months of life. These differences in microbiome composition are implicated in acute clinical conditions that disproportionately affect preterm infants, including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS). Probiotic supplementation initiated early in life is an effective prophylactic measure for preventing NEC, LOS, and other clinical concerns relevant to preterm infants. In parallel, reported benefits of probiotics on the preterm gut microbiome, metabolome, and immune function are beginning to emerge. This review summarizes the current literature on the influence of probiotics on the gut microbiome of preterm infants, outlines potential mechanisms by which these effects are exerted, and highlights important clinical considerations for determining the best practices for probiotic use in premature infants.
Employing pigs to decipher the host genetic effect on gut microbiome: advantages, challenges, and perspectives
Authors: Lusheng Huang, Congying Chen
Journal: Gut Microbes (2023)

The gut microbiota is a complex and diverse ecosystem comprised of trillions of microbes and plays an essential role in host's immunity, metabolism, and even behaviors. Environmental and host factors drive the huge variations in the gut microbiome among individuals. Here, we summarize accumulated evidences about host genetic effect on the gut microbial compositions with emphases on the correlation between host genetic kinship and the similarity of microbial compositions, heritability estimates of microbial taxa, and identification of genomic variants associated with the gut microbiome in pigs as well as in humans. A proportion of bacterial taxa have been reported to be heritable, and numerous variants associated with the diversity of the gut microbiota or specific taxa have been identified in both humans and pigs. LCT and ABO gene have been replicated in multiple studies, and its mechanism have been elucidated clearly. We also discuss the main advantages and challenges using pigs as experimental animals in exploring host genetic effect on the gut microbial composition and provided our insights on the perspectives in this area.
Multiomics analysis of human peripheral blood reveals marked molecular profiling changes caused by one night of sleep deprivation
Authors: Chongyang Chen, Jing Wang, Chao Yang, Haitao Yu, Bingge Zhang, Xiao Yang, Bocheng Xiong, Yongmei Xie, Shupeng Li, Zaijun Zhang, Feiqi Zhu, Jianjun Liu, Gong‐Ping Liu, Xifei Yang
Journal: MedComm (2023)

Sleep insufficiency is associated with various disorders; the molecular basis is unknown until now. Here, 14 males and 18 females were subjected to short-term (24 h) sleep deprivation, and donated fasting blood samples prior to (day 1) and following (days 2 and 3) short-term sleep deprivation. We used multiple omics techniques to examine changes in volunteers' blood samples that were subjected to integrated, biochemical, transcriptomic, proteomic, and metabolomic analyses. Sleep deprivation caused marked molecular changes (46.4% transcript genes, 59.3% proteins, and 55.6% metabolites) that incompletely reversed by day 3. The immune system in particular neutrophil-mediated processes associated with plasma superoxidase dismutase-1 and S100A8 gene expression was markedly affected. Sleep deprivation decreased melatonin levels and increased immune cells, inflammatory factors and c-reactive protein. By disease enrichment analysis, sleep deprivation induced signaling pathways for schizophrenia and neurodegenerative diseases enriched. In sum, this is the first multiomics approach to show that sleep deprivation causes prominent immune changes in humans, and clearly identified potential immune biomarkers associated with sleep deprivation. This study indicated that the blood profile following sleep disruption, such as may occur among shift workers, may induce immune and central nervous system dysfunction.
m6A readers ECT2/ECT3/ECT4 enhance mRNA stability through direct recruitment of the poly(A) binding proteins in Arabidopsis
Authors: Peizhe Song, Lianhuan Wei, Zixin Chen, Zhihe Cai, Qiang Lu, Chunling Wang, Enlin Tian, Guifang Jia
Journal: Genome biology (2023)

Abstract Background RNA N 6 -methyladenosine (m 6 A) modification is critical for plant growth and crop yield. m 6 A reader proteins can recognize m 6 A modifications to facilitate the functions of m 6 A in gene regulation. ECT2, ECT3, and ECT4 are m 6 A readers that are known to redundantly regulate trichome branching and leaf growth, but their molecular functions remain unclear. Results Here, we show that ECT2, ECT3, and ECT4 directly interact with each other in the cytoplasm and perform genetically redundant functions in abscisic acid (ABA) response regulation during seed germination and post-germination growth. We reveal that ECT2/ECT3/ECT4 promote the stabilization of their targeted m 6 A-modified mRNAs, but have no function in alternative polyadenylation and translation. We find that ECT2 directly interacts with the poly(A) binding proteins, PAB2 and PAB4, and maintains the stabilization of m 6 A-modified mRNAs. Disruption of ECT2/ECT3/ECT4 destabilizes mRNAs of ABA signaling-related genes, thereby promoting the accumulation of ABI5 and leading to ABA hypersensitivity. Conclusion Our study reveals a unified functional model of m 6 A mediated by m 6 A readers in plants. In this model, ECT2/ECT3/ECT4 promote stabilization of their target mRNAs in the cytoplasm.
Boosting genome editing efficiency in human cells and plants with novel LbCas12a variants
Authors: Liyang Zhang, Gen Li, Yingxiao Zhang, Yanhao Cheng, Nathaniel Roberts, Steve E. Glenn, Diane DeZwaan-McCabe, H. Tomas Rube, Jeff Manthey, Gary Coleman, Christopher A. Vakulskas, Yiping Qi
Journal: Genome biology (2023)

Cas12a (formerly known as Cpf1), the class II type V CRISPR nuclease, has been widely used for genome editing in mammalian cells and plants due to its distinct characteristics from Cas9. Despite being one of the most robust Cas12a nucleases, LbCas12a in general is less efficient than SpCas9 for genome editing in human cells, animals, and plants.